Biology subjects

Martin, C. M.

Publications and source records attributed to Martin, C. M..

4 recordsLinked to original sources

bioRxiv2025

Hepatocyte FGF21 is not required for fasting-induced metabolic responses but guides protein appetite after energy depletion

Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we studied mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes did not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncovered a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.

physiology↗

bioRxiv2024

Effect of thermoneutral housing on MASLD severity, hepatic gene expression, and BAT activation during beta3-adrenergic stimulation in mice

Metabolic dysfunction-associated steatotic liver disease (MASLD), and its more advanced stage metabolic dysfunction-associated steatohepatitis, is the most common chronic liver disease, constituting a major public health issue. No medication is approved for MASLD treatment, and relevant preclinical models are needed to define molecular mechanisms underlying MASLD pathogenesis, and evaluate therapeutic approaches. Here we demonstrated that compared to standard temperature housing, thermoneutral housing aggravated western diet (WD)-induced obesity, diabetes, and steatosis in male mice, which was associated with increased hepatic expression of inflammation- and fibrosis-related genes. Accordingly, compared to standard-housed mice, thermoneutral-housed WD-fed mice developed more severe hepatic inflammation and fibrosis. The liver is the central metabolic organ in whole-body metabolic homeostasis. We used thermoneutrally housed mice with WD-induced MASLD to examine the effect of MASLD during {beta}3- adrenergic stimulation, and found that diet-induced MASLD was associated with defective inter- organ metabolic cross-talk, leading to impaired brown adipose tissue activation. HighlightsO_LIThermoneutral housing promotes WD-induced obesity and MASLD in mice C_LIO_LIThermoneutral housing fosters WD-induced change in gene expression C_LIO_LIThermoneutral housing fosters hepatic inflammation and fibrosis C_LIO_LIMASLD is associated with defective BAT response to {beta}3-adrenergic stimulation C_LI

physiology↗

bioRxiv2024

Design, Synthesis, and Efficacy of Novel Trojan Horse Compounds Targeting Metabolic Vulnerabilities in Prostate Cancer

Background and purposeProstate cancer (PCa) remains a significant global health concern, warranting the development of new therapeutic strategies.1 Metabolic reprogramming, an emerging hallmark of PCa progression characterized by aberrant nutrient utilization, has become a focus area in developing new treatments. Among these metabolic alterations, the Warburg effect--a shift towards aerobic glycolysis-- has garnered significant attention as a potential therapeutic target. 2 To explore this, we synthesised a novel class of Trojan Horse compounds designed to exploit the unique metabolic profile of cancer cells and investigated their therapeutic potential using cell based models of PCa, as a proof of principle strategy. Experimental approachPreliminary cytotoxicity analysis revealed that native menadione had low efficacy against PCa cells. Consequently, we developed glucose and fatty acid conjugated TH compounds based on a menadione backbone. A library of six novel menadione-glucose and fatty acid-based TH compounds were synthesized through copper-catalysed click chemistry. These compounds were designed to mimic a desirable fuel source (sugar or fatty acid) acting as a "Trojan Horse" for PCa cells to modulate their metabolism. The cytotoxic and selective effects of the TH compounds were evaluated in PCa and non-malignant cell lines cultured under varying glucose conditions. To elucidate the mechanisms of action, mitochondrial bioenergetics, metabolic phenotyping, and metabolomic profiling were employed to assess the impact of each TH compound on cellular metabolism. Key resultsTH3 (glucose) and TH5 (fatty acid) compounds demonstrated promising cytotoxicity for PCa cell lines, with TH5 exhibiting superior selectivity compared to TH3 and particularly over native menadione. Despite these results, alterations in metabolic phenotypes were only modest. Mitochondrial bioenergetics were notably impacted by TH5, while ROS levels remained stable post-treatment, likely due to an increase in ROS scavenging amino acids as a compensatory antioxidant response. Conclusion and ImplicationsThis study demonstrates the potential of employing glucose and fatty acid-conjugated compounds to target the unique metabolic features of PCa. These findings offer promising new avenues for further investigation, aimed at optimizing efficacy and selectivity of these compounds for clinical translation. The intricate relationship between ROS production and antioxidant defence mechanisms emphasizes the complex nature of metabolic interventions in cancer. Elucidating the mode of action and exploring molecular modifications may pave the way for personalised and targeted PCa therapies, ultimately improving patient outcomes and mitigating the global burden of this disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/610353v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1af7915org.highwire.dtl.DTLVardef@1368f16org.highwire.dtl.DTLVardef@ebfe63org.highwire.dtl.DTLVardef@18a181b_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance statementThis body of work gives critical insights into the metabolic vulnerabilities of prostate cancer (PCa), particularly of androgen-independent and metastatic disease, which currently present significant treatment challenges. By designing, synthesising and testing innovative menadione-based Trojan Horse compounds that target altered cancer cell metabolism, this research highlights a promising new therapeutic strategy against malignant cells. The findings underscore the potential for metabolic reprogramming to combat treatment resistance in advanced PCa, paving the way forward for the development of new drugs and personalised treatment approaches. This could lead to improved outcomes for patients with currently untreatable forms of the disease.

cancer biology↗

bioRxiv2023

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

biochemistry↗